CB2 cannabinoid receptor is a novel target for third-generation selective estrogen receptor modulators bazedoxifene and lasofoxifene

Kumar, Pritesh; Song, Zhao-Hui

doi:10.1016/j.bbrc.2013.11.071

Cited by 15 publications

(12 citation statements)

References 20 publications

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“…17-β-Estradiol could be assumed to increase the expression of CB-2 receptors, as has been previously observed in osteoclasts in vitro (24), or it is possible that estrogens act through other, non-genomic mechanisms (26). Recent studies also show that selective estrogen modulators, raloxifene (27), bazedoxifene and lasofoxifene, behave as CB-2 inverse agonists (28), which may also be true for 17-β-estradiol and would correlate with the present results.…”

Section: Discussionsupporting

confidence: 86%

A synergistic interaction of 17-β-estradiol with specific cannabinoid receptor type 2 antagonist/inverse agonist on proliferation activity in primary human osteoblasts

et al. 2015

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Abstract. The bone remodeling process is influenced by various factors, including estrogens and transmitters of the endocannabinoid system. In osteoblasts, cannabinoid receptors 2 (CB-2) are expressed at a much higher level compared to CB-1 receptors. Previous studies have shown that estrogens could influence CB-2 receptor expression. In the present study, the possible interactions of a specific CB-2 agonist and a specific CB-2 antagonist/inverse agonist with 17-β-estradiol were investigated in primary human osteoblasts (HOB). HOB cells were cultured in phenol red-free osteoblast growth medium (37˚C, 5% CO 2 ). In their 5th passage, HOB were exposed to different concentrations of i) 17-β-estradiol (1, 10 and 100 nM); ii) a specific CB-2 agonist (R,S)-AM1241 (1 and 7.5 µM); and iii) a specific CB-2 antagonist/inverse agonist AM630 (10 µM) and to selected combinations of the substances. After 24 and 48 h of incubation, HOB proliferation activity was measured using a WST-8 assay. Alkaline phosphatase activity was also evaluated using spectrophotometry. Concomitant exposure of HOB to 17-β-estradiol (10 nM) and to specific CB-2 antagonist/inverse agonist (10 µM) showed similar HOB proliferation activity to HOB incubated with 17-β-estradiol only at a 100 nM concentration. By contrast, concomitant incubation of HOB with 17-β-estradiol (10 nM) and specific CB-2 agonist (7.5 µM) resulted in decreased HOB proliferation activity as compared to HOB incubated with 17-β-estradiol only (10 nM). Similar findings were observed after 24 and 48 h of incubation. In all the experiments, HOB successfully passed the alkaline phosphatase differentiation test. In conclusion, for the first time a synergistic interaction between 17-β-estradiol and specific CB-2 antagonist/inverse agonist was observed in HOB. Understanding the molecular pathways of this interaction would be of great importance in developing more efficient and safer drugs for treating or preventing bone diseases.

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Section: Discussionsupporting

confidence: 86%

A synergistic interaction of 17-β-estradiol with specific cannabinoid receptor type 2 antagonist/inverse agonist on proliferation activity in primary human osteoblasts

et al. 2015

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“…For example, some studies have suggested that both crude cannabis extract and THC inhibit the binding of estradiol to estradiol receptors in vivo (74,75). Recent studies showed that some estrogen receptor modulators can bind to cannabinoid receptors (76,77). These results have raised the possibility that THC could regulate histone methylation through ER signaling.…”

Section: Discussionmentioning

confidence: 99%

Histone Modifications Are Associated with Δ9-Tetrahydrocannabinol-mediated Alterations in Antigen-specific T Cell Responses

Yang¹,

Hegde²,

Rao³

et al. 2014

Journal of Biological Chemistry

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Background: Marijuana has been shown to have an immunomodulatory activity. Results: ChIP-Seq results show genome-wide changes in histone methylation in immune cells treated with THC. Conclusion: Histone modifications are associated with THC-mediated alterations in antigen-specific T cell response. Significance: This study provides insights into the potential role of epigenetic changes induced by THC in gene regulation.

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“…Interestingly, it should be noted that in this study, and as reported previously [17, 18], special assay conditions were needed to observe optimal CBR antagonism by SERMs. For example, assays were conducted at room temperature with a 30 min SERM pre-incubation period, followed by agonist exposure for 7 min.…”

Section: Discussionmentioning

confidence: 54%

“…However, due to the adverse effects of currently available drugs acting at CBRs, FDA approval of therapeutic cannabinoids unfortunately remains elusive. Recent studies by our group [16] and others [17, 18] have shown that several clinically available, FDA-approved drugs in the selective estrogen receptor modular (SERM) class (e.g. Z-Tamoxifen, Z-4-hydroxytamoxifen, and Raloxifen) also bind and modulate activity of CB1 and CB2Rs.…”

Section: Introductionmentioning

confidence: 99%

Tamoxifen Isomers and Metabolites Exhibit Distinct Affinity and Activity at Cannabinoid Receptors: Potential Scaffold for Drug Development

et al. 2016

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Tamoxifen (Tam) is a selective estrogen receptor (ER) modulator (SERM) that is an essential drug to treat ER-positive breast cancer. Aside from known actions at ERs, recent studies have suggested that some SERMs like Tam also exhibit novel activity at cannabinoid subtype 1 and 2 receptors (CB1R and CB2Rs). Interestingly, cis- (E-Tam) and trans- (Z-Tam) isomers of Tam exhibit over a 100-fold difference in affinity for ERs. Therefore, the current study assessed individual isomers of Tam and subsequent cytochrome P450 metabolic products, 4-hydroxytamoxifen (4OHT) and 4-hydroxy-N-desmethyl tamoxifen (End) for affinity and activity at CBRs. Results showed that Z-4OHT, but not Z-Tam or Z-End, exhibits higher affinity for both CB1 and CB2Rs relative to the E-isomer. Furthermore, Z- and E-isomers of Tam and 4OHT show slightly higher affinity for CB2Rs, while both End isomers are relatively CB1R-selective. When functional activity was assessed by G-protein activation and regulation of the downstream effector adenylyl cyclase, all isomers examined act as full CB1 and CB2R inverse agonists. Interestingly, Z-Tam appears to be more efficacious than the full inverse agonist AM630 at CB2Rs, while both Z-Tam and Z-End exhibit characteristics of insurmountable antagonism at CB1 and CB2Rs, respectively. Collectively, these results suggest that the SERMs Tam, 4OHT and End elicit ER-independent actions via CBRs in an isomer-specific manner. As such, this novel structural scaffold might be used to develop therapeutically useful drugs for treatment of a variety of diseases mediated via CBRs.

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CB2 cannabinoid receptor is a novel target for third-generation selective estrogen receptor modulators bazedoxifene and lasofoxifene

Cited by 15 publications

References 20 publications

A synergistic interaction of 17-β-estradiol with specific cannabinoid receptor type 2 antagonist/inverse agonist on proliferation activity in primary human osteoblasts

A synergistic interaction of 17-β-estradiol with specific cannabinoid receptor type 2 antagonist/inverse agonist on proliferation activity in primary human osteoblasts

Histone Modifications Are Associated with Δ9-Tetrahydrocannabinol-mediated Alterations in Antigen-specific T Cell Responses

Tamoxifen Isomers and Metabolites Exhibit Distinct Affinity and Activity at Cannabinoid Receptors: Potential Scaffold for Drug Development

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